Stromal Endothelial Cells Establish a Bidirectional Crosstalk with Chronic Lymphocytic Leukemia Cells through the TNF-Related Factors BAFF, APRIL, and CD40L.

J Immunol. 2012 May 16;

Authors: Cols M, Barra CM, He B, Puga I, Xu W, Chiu A, Tam W, Knowles DM, Dillon SR, Leonard JP, Furman RR, Chen K, Cerutti A

Abstract

Chronic lymphocytic leukemia (CLL) is a clonal B cell disorder of unknown origin. Accessory signals from the microenvironment are critical for the survival, expansion, and progression of malignant B cells. We found that the CLL stroma included microvascular endothelial cells (MVECs) expressing BAFF and APRIL, two TNF family members related to the T cell-associated B cell-stimulating molecule CD40L. Constitutive release of soluble BAFF and APRIL increased upon engagement of CD40 on MVECs by CD40L aberrantly expressed on CLL cells. In addition to enhancing MVEC expression of CD40, leukemic CD40L induced cleavases that elicited intracellular processing of pro-BAFF and pro-APRIL proteins in MVECs. The resulting soluble BAFF and APRIL proteins delivered survival, activation, Ig gene remodeling, and differentiation signals by stimulating CLL cells through TACI, BAFF-R, and BCMA receptors. BAFF and APRIL further amplified CLL cell survival by upregulating the expression of leukemic CD40L. Inhibition of TACI, BCMA, and BAFF-R expression on CLL cells; abrogation of CD40 expression in MVECs; or suppression of BAFF and APRIL cleavases in MVECs reduced the survival and diversification of malignant B cells. These data indicate that BAFF, APRIL, and CD40L form a CLL-enhancing bidirectional signaling network linking neoplastic B cells with the microvascular stroma.

PMID: 22593611 [PubMed - as supplied by publisher]

Humoral and Cellular Capsid-Specific Immune Responses to Adeno-Associated Virus Type 1 in Randomized Healthy Donors.

J Immunol. 2012 May 16;

Authors: Veron P, Leborgne C, Monteilhet V, Boutin S, Martin S, Moullier P, Masurier C

Abstract

A major impediment to the use of adeno-associated virus (AAV)-mediated gene delivery to muscle in clinical applications is the pre-existing immune responses against the vector. Pre-existing humoral response to different AAV serotypes is now well documented. In contrast, cellular responses to AAV capsid have not been analyzed in a systematic manner, despite the risk of T cell reactivation upon gene transfer. AAV1 has been widely used in humans to target muscle. In this study, we analyzed PBMCs and sera of healthy donors for the presence of AAV1 capsid-specific T cell responses and AAV1 neutralizing factors. Approximately 30% of donors presented AAV1 capsid-specific T cells, mainly effector memory CD8(+) cells. IFN-γ-producing cells were also observed among effector memory CD4(+) cells for two of these donors. Moreover, to our knowledge, this study shows for the first time on a large cohort that there was no correlation between AAV1-specific T cell and humoral responses. Indeed, most donors presenting specific Ig and neutralizing factors were negative for cellular response (and vice versa). These new data raise the question of prescreening patients not only for the humoral response, but also for the cellular response. Clearly, a better understanding of the natural immunology of AAV serotypes will allow us to improve AAV gene therapy and make it an efficient treatment for genetic disease.

PMID: 22593612 [PubMed - as supplied by publisher]

An In Vivo IL-7 Requirement for Peripheral Foxp3+ Regulatory T Cell Homeostasis.

J Immunol. 2012 May 16;

Authors: Kim GY, Ligons DL, Hong C, Luckey MA, Keller HR, Tai X, Lucas PJ, Gress RE, Park JH

Abstract

All T cells are dependent on IL-7 for their development and for homeostasis. Foxp3(+) regulatory T cells (Tregs) are unique among T cells in that they are dependent on IL-2. Whether such IL-2 dependency is distinct from or in addition to an IL-7 requirement has been a confounding issue, particularly because of the absence of an adequate experimental system to address this question. In this study, we present a novel in vivo mouse model where IL-2 expression is intact but IL-7 expression was geographically limited to the thymus. Consequently, IL-7 is not available in peripheral tissues. Such mice were generated by introducing a thymocyte-specific IL-7 transgene onto an IL-7 null background. In these mice, T cell development in the thymus, including Foxp3(+) Treg numbers, was completely restored, which correlates with the thymus-specific expression of transgenic IL-7. In peripheral cells, however, IL-7 expression was terminated, which resulted in a general paucity of T cells and a dramatic reduction of Foxp3(+) Treg numbers. Loss of Tregs was further accompanied by a significant reduction in Foxp3(+) expression levels. These data suggest that peripheral IL-7 is not only necessary for Treg survival but also for upregulating Foxp3 expression. Collectively, we assessed the effect of a selective peripheral IL-7 deficiency in the presence of a fully functional thymus, and we document a critical requirement for in vivo IL-7 in T cell maintenance and specifically in Foxp3(+) cell homeostasis.

PMID: 22593613 [PubMed - as supplied by publisher]

Enhanced Anti-Serpin Antibody Activity Inhibits Autoimmune Inflammation in Type 1 Diabetes.

J Immunol. 2012 May 16;

Authors: Czyzyk J, Henegariu O, Preston-Hurlburt P, Baldzizhar R, Fedorchuk C, Esplugues E, Bottomly K, Gorus FK, Herold K, Flavell RA

Abstract

Intracellular (clade B) OVA-serpin protease inhibitors play an important role in tissue homeostasis by protecting cells from death in response to hypo-osmotic stress, heat shock, and other stimuli. It is not known whether these serpins influence immunological tolerance and the risk for autoimmune diseases. We found that a fraction of young autoimmune diabetes-prone NOD mice had elevated levels of autoantibodies against a member of clade B family known as serpinB13. High levels of anti-serpinB13 Abs were accompanied by low levels of anti-insulin autoantibodies, reduced numbers of islet-associated T cells, and delayed onset of diabetes. Exposure to anti-serpinB13 mAb alone also decreased islet inflammation, and coadministration of this reagent and a suboptimal dose of anti-CD3 mAb accelerated recovery from diabetes. In a fashion similar to that discovered in the NOD model, a deficiency in humoral activity against serpinB13 was associated with early onset of human type 1 diabetes. These findings suggest that, in addition to limiting exposure to proteases within the cell, clade B serpins help to maintain homeostasis by inducing protective humoral immunity.

PMID: 22593614 [PubMed - as supplied by publisher]

Ethnicity and Nonalcoholic Fatty Liver Disease – Reply.

Hepatology. 2012 May 17;

Authors: Bambha K, Bass NM

PMID: 22605462 [PubMed - as supplied by publisher]

Crosstalk between the hepatologist and the cardiologist: a future place for the lithocholic acid as a coronary atheroma risk factor?

Hepatology. 2012 May 17;

Authors: Duboc H, Aelion H, Rainteau D, Rajca S, Sokol H, Humbert L, Farabos D, Coffin B, Weber S, Porcher R, Varenne O, Duboc D

PMID: 22605482 [PubMed - as supplied by publisher]

Hedgehog-responsive progenitors: predictors of liver outcomes?

Hepatology. 2012 May 17;

Authors: Syn WK

PMID: 22605508 [PubMed - as supplied by publisher]

Response letter to: Hedgehog-responsive progenitors: predictors of liver outcomes?

Hepatology. 2012 May 17;

Authors: Sancho-Bru P

PMID: 22605512 [PubMed - as supplied by publisher]

Maintenance drugs to treat opioid dependence.

BMJ. 2012;344:e2823

Authors: Farrell M, Wodak A, Gowing L

PMID: 22589497 [PubMed - in process]

Action on Hearing Loss needs your support.

BMJ. 2012;344:e3059

Authors: Leverton T

PMID: 22589498 [PubMed - in process]

Defining the fingertip unit.

BMJ. 2012;344:e3061

Authors: Finlay AY

PMID: 22589499 [PubMed - in process]

Effectiveness of dementia follow-up care by memory clinics or general practitioners: randomised controlled trial.

BMJ. 2012;344:e3086

Authors: Meeuwsen EJ, Melis RJ, Van Der Aa GC, Golüke-Willemse GA, De Leest BJ, Van Raak FH, Schölzel-Dorenbos CJ, Verheijen DC, Verhey FR, Visser MC, Wolfs CA, Adang EM, Olde Rikkert MG

Abstract

OBJECTIVE: To examine the effectiveness of post-diagnosis dementia treatment and coordination of care by memory clinics compared with general practitioners.

DESIGN: Multicentre randomised controlled trial.

SETTING: Nine memory clinics and 159 general practitioners in the Netherlands.

PARTICIPANTS: 175 patients with a new diagnosis of mild to moderate dementia living in the community and their informal caregivers.

INTERVENTIONS: Usual care provided by memory clinic or general practitioner.

MAIN OUTCOME MEASURES: Caregiver rated quality of life of the patient measured with the quality of life in Alzheimer’s disease instrument and self perceived burden of the informal caregiver measured with the sense of competence questionnaire (intention to treat analysis).

RESULTS: The quality of life of the patients in the memory clinic group was 0.5 (95% confidence interval -0.7 to 1.6) points higher than in the general practitioner group. Caregivers’ burden was 2.4 (-5.8 to 1.0) points lower in the memory clinic group than in the general practitioner group.

CONCLUSION: No evidence was found that memory clinics were more effective than general practitioners with regard to post-diagnosis treatment and coordination care for patients with dementia. Without further evidence on the effectiveness of these modalities, other arguments, such as cost minimisation, patients’ preferences, or regional health service planning, can determine which type of dementia care is offered.

TRIAL REGISTRATION: Clinical trials NCT00554047.

PMID: 22589500 [PubMed - in process]

Strengthening primary healthcare in India: white paper on opportunities for partnership.

BMJ. 2012;344:e3151

Authors: Rao M, Mant D

PMID: 22589501 [PubMed - in process]

A 64 year old woman with headache and breathlessness.

BMJ. 2012;344:e3158

Authors: Lord R, Flight W, Sweeney A, Chaudhry N

PMID: 22589502 [PubMed - in process]

The risks of reducing current salt levels.

BMJ. 2012;344:e3205

Authors: Satin M

PMID: 22589503 [PubMed - in process]

Policy change on VZIG in the US to match UK recommendations.

BMJ. 2012;344:e3207

Authors: Macmahon E

PMID: 22589504 [PubMed - in process]

We need to move away from relying on drugs to prevent lifestyle induced chronic disease.

BMJ. 2012;344:e3214

Authors: Stamatakis E, Weiler R

PMID: 22589505 [PubMed - in process]

Editorial ignored 17 reviews on wind turbines and health.

BMJ. 2012;344:e3366

Authors: Chapman S

PMID: 22589506 [PubMed - in process]

Authors’ reply to Chapman.

BMJ. 2012;344:e3367

Authors: Hanning CD, Evans A

PMID: 22589507 [PubMed - in process]

Time for rapid testing for streptococcus B during labour.

BMJ. 2012;344:e3368

Authors: Olver WJ

PMID: 22589508 [PubMed - in process]

Existing classes of antibiotics are probably the best we will ever have.

BMJ. 2012;344:e3369

Authors: Cormican M, Vellinga A

PMID: 22589509 [PubMed - in process]

Towards greater transparency in the life sciences.

BMJ. 2012;344:e3371

Authors: Thompson R, Khanna D

PMID: 22589510 [PubMed - in process]

Facts were not entirely correct.

BMJ. 2012;344:e3378

Authors: Robison C

PMID: 22589511 [PubMed - in process]

Surgical application of smartphones.

BMJ. 2012;344:e3379

Authors: Saripanidis S

PMID: 22589512 [PubMed - in process]

Group B Strep Support replies to Margaret McCartney.

BMJ. 2012;344:e3381

Authors: Steer P, Bedford Russell A, McCartney AC, Cox P, Plumb J

PMID: 22589513 [PubMed - in process]

Don’t ignore preventive message of baby Jayden’s case.

BMJ. 2012;344:e3386

Authors: Lucas PJ, Jessiman T, Cameron A

PMID: 22589514 [PubMed - in process]

Strengthening primary healthcare in India.

BMJ. 2012;344:e3410

Authors: Dandona L, Prasad J

PMID: 22589515 [PubMed - in process]

Insecticide resistance threatens malaria control programmes, WHO says.

BMJ. 2012;344:e3416

Authors: Moszynski P

PMID: 22589516 [PubMed - in process]

Medicine is our vocation.

BMJ. 2012;344:e3418

Authors: Spence D

PMID: 22589517 [PubMed - in process]

EU law forces UK ministers to rethink food labelling.

BMJ. 2012;344:e3422

Authors: Kmietowicz Z

PMID: 22589518 [PubMed - in process]

Should childhood vaccination be mandatory? Yes.

BMJ. 2012;344:e2434

Authors: Offit PA

PMID: 22589519 [PubMed - in process]

Should childhood vaccination be mandatory? No.

BMJ. 2012;344:e2435

Authors: Salisbury DM

PMID: 22589520 [PubMed - in process]

Food policies for healthy populations and healthy economies.

BMJ. 2012;344:e2801

Authors: Hawkes C

PMID: 22589521 [PubMed - in process]

Taxing unhealthy food and drinks to improve health.

BMJ. 2012;344:e2931

Authors: Mytton OT, Clarke D, Rayner M

PMID: 22589522 [PubMed - in process]

Allocation of NHS resources: are some patients more equal than others?

BMJ. 2012;344:e3362

Authors: Hawkes N

PMID: 22589525 [PubMed - in process]

Can a simple blood test really predict breast cancer?

BMJ. 2012;344:e3374

Authors: McCartney M

PMID: 22589526 [PubMed - in process]

Netherlands tops European healthcare league, with UK coming in at 12th.

BMJ. 2012;344:e3430

Authors: Watson R

PMID: 22589527 [PubMed - in process]

EU tightens drug safety law before it is even implemented.

BMJ. 2012;344:e3455

Authors: Watson R

PMID: 22589528 [PubMed - in process]

Device regulator is told to improve its safety monitoring after breast implant debacle.

BMJ. 2012;344:e3456

Authors: Torjesen I

PMID: 22589529 [PubMed - in process]

UK doctors vote on industrial action for first time in 37 years.

BMJ. 2012;344:e3457

Authors: Jaques H

PMID: 22589530 [PubMed - in process]

Pfizer Australia faces scrutiny over atorvastatin advertising campaign.

BMJ. 2012;344:e3463

Authors: Sweet M

PMID: 22589531 [PubMed - in process]

A system-wide challenge for UK food policy.

BMJ. 2012;344:e3414

Authors: Jebb SA

PMID: 22589532 [PubMed - in process]

Pancreatic adenocarcinoma.

BMJ. 2012;344:e2476

Authors: Bond-Smith G, Banga N, Hammond TM, Imber CJ

PMID: 22592847 [PubMed - in process]

All you need to read in the other general journals.

BMJ. 2012;344:e3359

Authors:

PMID: 22592848 [PubMed - in process]

David Southall: anatomy of a wrecked career.

BMJ. 2012;344:e3377

Authors: Dyer C

PMID: 22592849 [PubMed - in process]

The British government’s Troubled Families Programme.

BMJ. 2012;344:e3403

Authors: Fletcher A, Gardner F, McKee M, Bonell C

PMID: 22592850 [PubMed - in process]

Experts launch Europe-wide drive to highlight dangers of alcohol.

BMJ. 2012;344:e3424

Authors: O’Dowd A

PMID: 22592851 [PubMed - in process]

Discrimination against doctors with HIV must end.

BMJ. 2012;344:e3440

Authors: Ma R

PMID: 22592852 [PubMed - in process]

Information commissioner condemns health secretary for failing to publish risk register.

BMJ. 2012;344:e3480

Authors: Dyer C

PMID: 22592904 [PubMed - in process]

US citizens are less healthy but living longer, report says.

BMJ. 2012;344:e3481

Authors: Roehr B

PMID: 22592905 [PubMed - in process]

Lack of specialist diabetes teams in hospitals is “absolutely disgraceful,” says NHS clinical lead.

BMJ. 2012;344:e3449

Authors: Torjesen I

PMID: 22592940 [PubMed - in process]

Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence.

BMJ. 2012;344:e2088

Authors: Thangaratinam S, Rogozinska E, Jolly K, Glinkowski S, Roseboom T, Tomlinson JW, Kunz R, Mol BW, Coomarasamy A, Khan KS

Abstract

OBJECTIVE: To evaluate the effects of dietary and lifestyle interventions in pregnancy on maternal and fetal weight and to quantify the effects of these interventions on obstetric outcomes.

DESIGN: Systematic review and meta-analysis.

DATA SOURCES: Major databases from inception to January 2012 without language restrictions.

STUDY SELECTION: Randomised controlled trials that evaluated any dietary or lifestyle interventions with potential to influence maternal weight during pregnancy and outcomes of pregnancy.

DATA SYNTHESIS: Results summarised as relative risks for dichotomous data and mean differences for continuous data.

RESULTS: We identified 44 relevant randomised controlled trials (7278 women) evaluating three categories of interventions: diet, physical activity, and a mixed approach. Overall, there was 1.42 kg reduction (95% confidence interval 0.95 to 1.89 kg) in gestational weight gain with any intervention compared with control. With all interventions combined, there were no significant differences in birth weight (mean difference -50 g, -100 to 0 g) and the incidence of large for gestational age (relative risk 0.85, 0.66 to 1.09) or small for gestational age (1.00, 0.78 to 1.28) babies between the groups, though by itself physical activity was associated with reduced birth weight (mean difference -60 g, -120 to -10 g). Interventions were associated with a reduced the risk of pre-eclampsia (0.74, 0.60 to 0.92) and shoulder dystocia (0.39, 0.22 to 0.70), with no significant effect on other critically important outcomes. Dietary intervention resulted in the largest reduction in maternal gestational weight gain (3.84 kg, 2.45 to 5.22 kg), with improved pregnancy outcomes compared with other interventions. The overall evidence rating was low to very low for important outcomes such as pre-eclampsia, gestational diabetes, gestational hypertension, and preterm delivery.

CONCLUSIONS: Dietary and lifestyle interventions in pregnancy can reduce maternal gestational weight gain and improve outcomes for both mother and baby. Among the interventions, those based on diet are the most effective and are associated with reductions in maternal gestational weight gain and improved obstetric outcomes.

PMID: 22596383 [PubMed - in process]

How should women be advised on weight management in pregnancy?

BMJ. 2012;344:e2774

Authors: Poston L, Chappell LC

PMID: 22596384 [PubMed - in process]

Can Twitter predict disease outbreaks?

BMJ. 2012;344:e2353

Authors: St Louis C, Zorlu G

PMID: 22597352 [PubMed - in process]

The scatter of research: cross sectional comparison of randomised trials and systematic reviews across specialties.

BMJ. 2012;344:e3223

Authors: Hoffmann T, Erueti C, Thorning S, Glasziou P

Abstract

OBJECTIVE: To estimate the degree of scatter of reports of randomised trials and systematic reviews, and how the scatter differs among medical specialties and subspecialties.

DESIGN: Cross sectional analysis.

DATA SOURCE: PubMed for all disease relevant randomised trials and systematic reviews published in 2009.

STUDY SELECTION: Randomised trials and systematic reviews of the nine diseases or disorders with the highest burden of disease, and the broader category of disease to which each belonged.

RESULTS: The scatter across journals varied considerably among specialties and subspecialties: otolaryngology had the least scatter (363 trials across 167 journals) and neurology the most (2770 trials across 896 journals). In only three subspecialties (lung cancer, chronic obstructive pulmonary disease, hearing loss) were 10 or fewer journals needed to locate 50% of trials. The scatter was less for systematic reviews: hearing loss had the least scatter (10 reviews across nine journals) and cancer the most (670 reviews across 279 journals). For some specialties and subspecialties the papers were concentrated in specialty journals; whereas for others, few of the top 10 journals were a specialty journal for that area. Generally, little overlap occurred between the top 10 journals publishing trials and those publishing systematic reviews. The number of journals required to find all trials or reviews was highly correlated (r=0.97) with the number of papers for each specialty/subspecialty.

CONCLUSIONS: Publication rates of speciality relevant trials vary widely, from one to seven trials per day, and are scattered across hundreds of general and specialty journals. Although systematic reviews reduce the extent of scatter, they are still widely scattered and mostly in different journals to those of randomised trials. Personal subscriptions to journals, which are insufficient for keeping up to date with knowledge, need to be supplemented by other methods such as journal scanning services or systems that cover sufficient journals and filter articles for quality and relevance. Few current systems seem adequate.

PMID: 22597353 [PubMed - in process]

India’s parliamentary panel sees nexus between drug regulators, manufacturers, and doctors.

BMJ. 2012;344:e3451

Authors: Mudur G

PMID: 22597354 [PubMed - in process]

Euro MPs refuse to approve medicines agency’s accounts until they tighten rules on conflicts of interest.

BMJ. 2012;344:e3495

Authors: Watson R

PMID: 22597355 [PubMed - in process]

Syrian doctors tell charity that “being caught with patients is like being caught with a weapon”.

BMJ. 2012;344:e3506

Authors: Gulland A

PMID: 22597759 [PubMed - in process]

Lack of Microsomal Prostaglandin E2 Synthase-1 in Bone Marrow Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality after Acute Myocardial Infarction.

Circulation. 2012 May 15;

Authors: Degousee N, Simpson J, Fazel S, Scholich K, Angoulvant D, Angioni C, Schmidt H, Korotkova M, Stefanski E, Wang XH, Lindsay TF, Ofek E, Pierre S, Butany J, Jakobsson PJ, Keating A, Li RK, Nahrendorf M, Geisslinger G, Backx PH, Rubin BB

Abstract

BACKGROUND: Microsomal prostaglandin E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes PGE(2) biosynthesis and is expressed by leukocytes, cardiac myocytes and cardiac fibroblasts. Ptges(-/-) mice develop more left ventricle (LV) dilation, worse LV contractile function and higher LV end diastolic pressure (LVEDP) than Ptges(+/+) mice after MI. In this study, we define the role of mPGES-1 in bone marrow derived leukocytes in the recovery of LV function after coronary ligation. METHODS AND RESULTS: Cardiac structure and function in Ptges(+/+) mice with Ptges(+/+) bone marrow (BM(+/+)) and Ptges(+/+) mice with Ptges(-/-) BM (BM(-/-)) was assessed by morphometric analysis, echocardiography and invasive hemodynamics before, 7 and 28 days after MI. Prostaglandin levels and prostaglandin biosynthetic enzyme gene expression were measured by LC-MS/MS and real time PCR, immunoblotting, immunohistochemistry and immunofluorescence microscopy, respectively. After MI, BM(-/-) mice have more LV dilation, worse LV systolic and diastolic function, higher LVEDP, more cardiomyocyte hypertrophy and higher mortality, but similar infarct size and pulmonary edema than BM(+/+) mice. BM(-/-) mice also have higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM(+/+) mice. Levels of PGE(2) are higher in the infarct and viable myocardium of BM(-/-) than BM(+/+) mice. CONCLUSIONS: Lack of mPGES-1 in bone marrow derived leukocytes negatively regulates COX-1 expression, PGE(2) biosynthesis and inflammation in the infarct, and leads to impaired LV function, adverse LV remodeling and decreased survival after acute MI.

PMID: 22589381 [PubMed - as supplied by publisher]

Prostaglandin E2 in Remote Control of Myocardial Remodeling.

Circulation. 2012 May 15;

Authors: Sun H, Wang Y

Abstract

Despite the advance in treatment of acute myocardial infarction (MI) with timely reperfusion of ischemic myocardium, coronary artery disease remains a leading cause of morbidity and mortality worldwide. In patients survived acute MI, heart undergoes a remodeling process characterized by changing in size, shape, structure, and function. The progressive ventricular dilation, wall thinning, fibrosis, together with loss of contractile function lead to life-threatening heart failure and arrhythmia. Therefore understanding the process of pathological remodeling in post-MI hearts is of paramount importance. It is well established that inflammatory response is elicited by MI and contributes significantly to cardiac remodeling. At the onset of MI injury, inflammatory leukocytes produced in bone marrow are mobilized and infiltrate the myocardium from circulation. The locally targeted leukocytes can be beneficial to wound healing by removing dead cells and matrix debris. However, prolonged inflammation may also contribute to additional cell death and scar formation due to fibrosis. Therefore inflammatory response has to be precisely controlled and timely resolved to avoid adverse remodeling in the post-infarct heart (1,2). As a result, modulating inflammatory response has been considered a potential therapeutic approach to preserve and recover heart function after MI (3,4). A great deal of effort has been made to understand the cellular and molecular mechanisms of inflammatory response following MI (2,5-8). (SELECT FULL TEXT TO CONTINUE).

PMID: 22589382 [PubMed - as supplied by publisher]

Racial and Ethnic Differences in Wait-List Outcomes in Patients Listed for Heart Transplantation in the United States.

Circulation. 2012 May 15;

Authors: Singh TP, Almond CS, Taylor DO, Milliren CE, Graham DA

Abstract

BACKGROUND: Racial differences in long-term survival after heart transplant (HT) are well known. We sought to assess racial/ethnic differences in wait-list outcomes among patients listed for HT in the United States (US) in the current era. METHODS AND RESULTS: We compared wait-list and post-transplant in-hospital mortality among White, Black and Hispanic patients ≥18 yrs old listed for their primary HT in the US between July 2006 and September 2010. Of 10,377 patients analyzed, 71% were White, 21% Black and 8% were Hispanic. Black and Hispanic patients were more likely to be listed with higher urgency (listing status 1A/1B) compared to White patients (P<0.001). Overall, 10.5% of White, 11.6% of Black and 13.4% of Hispanic candidates died on the wait-list or became too sick to transplant within 1-yr of listing. After adjusting for baseline risk factors, Hispanic patients were at higher risk of wait-list mortality (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.23, 1.85) compared to White patients but not Black patients (HR 1.13, 95% CI 0.97, 1.31). Compared to White HT recipients, post-transplant in-hospital mortality was higher in Black recipients (Odds ratio [OR] 1.53, 95% CI 1.15, 2.03) but was not different in Hispanic recipients (OR 0.78, 95% CI 0.48, 1.29). CONCLUSIONS: Hispanic patients listed for HT in the US appear to be at higher risk of dying on the wait-list or becoming too sick to transplant compared to White patients. Black patients are not at higher risk of wait-list mortality but have higher early post-transplant mortality.

PMID: 22589383 [PubMed - as supplied by publisher]

Persistent Renal Damage after Contrast-Induced Acute Kidney Injury: Incidence, Evolution, Risk Factors and Prognosis.

Circulation. 2012 May 16;

Authors: Maioli M, Toso A, Leoncini M, Gallopin M, Musilli N, Bellandi F

Abstract

BACKGROUND: The temporal evolution of renal function in patients with acute kidney injury after contrast medium (CI-AKI) is not well known. The aim of this observational study was to evaluate the incidence, risk factors and prognostic implications of persistent renal damage (RD) in patients with pre-existent moderate-to-severe renal dysfunction. METHODS AND RESULTS: From June 2003 to March 2008, 3986 patients underwent coronary angiography at our institution; 1490/3986 had an estimated creatinine clearance <60 ml/min and were enrolled. CI-AKI was defined as an absolute increase ≥0.5 mg/dl over baseline serum creatinine within 3 days after the administration of contrast medium (Iodixanol). In patients who developed CI-AKI, persistent RD was defined as a relative decrease of creatinine clearance ≥25% over baseline at 3 months. Patients whose creatinine clearance returned to baseline (or nearly) were classified as transient RD. The overall incidence of CI-AKI was 12.1% and persistent RD occurred in 18.6% of CI-AKI patients. At Cox regression analysis, nephropathy risk score ≥17, left ventricular ejection fraction ≤30% and increased value of serum creatinine ≥1.5 fold from baseline within five days, were found to be significant risk factors for persistent RD. At five years, the incidence of death was significantly higher in patients with persistent RD than both in patients with transient RD (p=.015) and in those without CI-AKI (p=.0001). A similar trend was observed for the combined endpoint of death, dialysis and cardiovascular events. CONCLUSIONS: These results suggest that CI-AKI is not always a transient, benign creatininopathy, but rather a direct cause of worsening renal function. The occurrence of CI-AKI can identify patients at increased risk of cardiovascular events.

PMID: 22592896 [PubMed - as supplied by publisher]

Impaired Autophagosome Clearance Contributes to Cardiomyocyte Death in Ischemia-Reperfusion Injury.

Circulation. 2012 May 16;

Authors: Ma X, Liu H, Foyil SR, Godar RJ, Weinheimer CJ, Hill JA, Diwan A

Abstract

BACKGROUND: In myocardial ischemia, induction of autophagy via the AMP-induced protein kinase (AMPK) pathway is protective, whereas reperfusion stimulates autophagy with BECLIN-1 upregulation, and is implicated in causing cell death. We examined flux through the macro-autophagy pathway as a determinant of the discrepant outcomes in cardiomyocyte cell death in this setting METHODS AND RESULTS: Reversible left anterior descending coronary artery ligation was performed in mice with cardiomyocyte-restricted expression of GFP-tagged microtubule associated protein light chain-3 (LC3) to induce ischemia (120 minutes) or ischemia-reperfusion (IR, 30-90 minutes) with saline or chloroquine (CQ) pretreatment (n=4/group). Autophagosome clearance, assessed as the ratio of punctate LC3 abundance in saline to CQ treated samples was markedly impaired with IR as compared with sham controls. Reoxygenation increased cell death in neonatal rat cardiomyocytes (NRCMs) as compared with hypoxia alone; markedly increased autophagosomes but not autolysosomes (assessed as punctate dual fluorescent mCherry-GFP tandem tagged LC3 expression); and impaired clearance of polyglutamine aggregates, indicating impaired autophagic flux. The resultant autophagosome accumulation was associated with increased reactive oxygen species (ROS) and mitochondrial permeabilization leading to cell death, which was attenuated by cyclosporine A pretreatment. Hypoxia-reoxygenation injury was accompanied by ROS-mediated BECLIN-1 upregulation and reduction in Lysosome Associated Membrane Protein-2 (LAMP2), a critical determinant of autophagosome-lysosome fusion. Restoration of LAMP2 levels synergizes with partial BECLIN-1 knockdown to restore autophagosome processing and attenuate cell death following hypoxia-reoxygenation. CONCLUSIONS: Ischemia-reperfusion injury impairs autophagosome clearance mediated in part by ROS-induced decline in LAMP2 and upregulation of BECLIN-1, contributing to increased cardiomyocyte death.

PMID: 22592897 [PubMed - as supplied by publisher]

Reduced Endoglin Activity Limits Cardiac Fibrosis and Improves Survival in Heart Failure.

Circulation. 2012 May 16;

Authors: Kapur NK, Wilson S, Yunis AA, Qiao X, Mackey E, Paruchuri V, Baker C, Aronovitz MJ, Karumanchi SA, Letarte M, Kass DA, Mendelsohn ME, Karas RH

Abstract

BACKGROUND: Heart failure is a major cause of morbidity and mortality worldwide. The ubiquitously expressed cytokine, transforming growth factor beta-1 (TGFβ1), promotes cardiac fibrosis, an important component of progressive heart failure. Membrane-associated endoglin is a co-receptor for TGFβ1 signaling and has been studied in vascular remodeling and preeclampsia. We hypothesized that reduced endoglin expression may limit cardiac fibrosis in heart failure. METHODS AND RESULTS: We first report that endoglin expression is increased in the left ventricle (LV) of human subjects with heart failure and determined that endoglin is required for TGFβ1 signaling in human cardiac fibroblasts using neutralizing antibodies and a siRNA approach. We further identified that reduced endoglin expression attenuates cardiac fibrosis, preserves LV function, and improves survival in a mouse model of pressure-overload induced heart failure. Prior studies have shown that the extracellular domain of endoglin can be cleaved and released into the circulation as soluble endoglin (sEng), which disrupts TGFβ1 signaling in endothelium. We now demonstrate that sEng limits TGFβ1 signaling and Type I collagen synthesis in cardiac fibroblasts and further show that sEng treatment attenuates cardiac fibrosis in an in vivo model of heart failure. CONCLUSIONS: Our results identify endoglin as a critical component of TGFβ1 signaling in the cardiac fibroblast and that targeting endoglin attenuates cardiac fibrosis, thereby providing a potentially novel therapeutic approach for individuals with heart failure.

PMID: 22592898 [PubMed - as supplied by publisher]

Targeting Endoglin, an Auxiliary TGF-β Coreceptor, to Prevent Fibrosis and Heart Failure.

Circulation. 2012 May 16;

Authors: Benjamin IJ

Abstract

Over the past 25 years, cardiovascular medicine has witnessed substantial progress in our understanding of the molecular pathogenesis, genetic etiologies as well as in the design of more efficacious therapeutic interventions. These advances have resulted in the dramatic reduction in the mortality of heart disease, especially in industrialized societies. Notwithstanding, both the prevalence and incidence of heart failure remain staggeringly high, posing new challenges and opportunities for prevention, diagnosis and management. Defined as the inability of the heart, as a mechanical pump, to meet the peripheral metabolic demands, this syndrome has many complex pathophysiological interactions among systolic performance, ventricular relaxation, impairments of contractility, and diastolic dysfunction. Both acquired (i.e., acute myocardial infarction) and genetic factors (mutations in genes encoding structural proteins) contribute to this clinical pathology but the development of overt heart failure ominously increases morbidity and decreases life-span. (SELECT FULL TEXT TO CONTINUE).

PMID: 22592899 [PubMed - as supplied by publisher]

Off-Pump Coronary Artery Bypass Surgery is Associated with Worse Arterial and Saphenous Vein Graft Patency and Less Effective Revascularization: Results From the Veterans Affairs Randomized On/Off Bypass (ROOBY) Trial.

Circulation. 2012 May 16;

Authors: Hattler B, Messenger JC, Shroyer AL, Collins JF, Haugen SJ, Garcia JA, Baltz JH, Cleveland JC, Novitzky D, Grover FL

Abstract

BACKGROUND: The Department of Veterans Affairs Randomized On/Off Bypass (ROOBY) trial compared clinical and angiographic outcomes in off-pump versus on-pump coronary artery bypass graft (CABG) surgery to ascertain the relative efficacy of the two techniques. METHODS AND RESULTS: From February 2002 to May 2007, the ROOBY trial randomized 2,203 patients to off-pump vs. on-pump CABG. Follow-up angiography was obtained in 685 (62%) off-pump and 685 (62%) on-pump patients. Angiograms were analyzed (blinded to treatment) for FitzGibbon’s classification (A = widely patent, B = flow limited, O = occluded) and effective revascularization. Effective revascularization was defined as follows: all of the 3 major coronary territories with significant disease were revascularized by a FitzGibbon’s A quality graft to the major diseased artery and there were no new post-anastomotic lesions. Off-pump CABG resulted in lower FitzGibbon A patency rates than on-pump CABG for arterial conduits (85.8% vs. 91.4%, p = 0.003) and SVGs (72.7 vs. 80.4%, p < 0.001). Fewer off-pump patients were effectively revascularized (50.1% vs. 63.9% on-pump, p < 0.001). Within each major coronary territory, effective revascularization was worse off-pump than on-pump (p values all ≤ 0.001). The 1-year adverse cardiac event rate was 16.4% in patients with ineffective revascularization vs. 5.9% in patients with effective revascularization (p <0.001). CONCLUSIONS: Off-pump CABG resulted in significantly lower FitzGibbon A patency for arterial and SVG conduits and less effective revascularization than on-pump CABG. At 1-year, patients with less effective revascularization had higher adverse event rates. CLINICAL TRIAL REGISTRATION INFORMATION: clinicaltrials.gov; Identifier: NCT00032630.

PMID: 22592900 [PubMed - as supplied by publisher]

Graft Patency Following Off-Pump Coronary Artery Bypass Surgery.

Circulation. 2012 May 16;

Authors: Thourani VH, Guyton RA

Abstract

For the past few decades, coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) and cardioplegic arrest has been considered the standard for surgical coronary revascularization. Since the mid-1990s, there has been increased interest in avoiding the use of extracorporeal circulation and the bypass circuit during construction of the distal anastomoses. This interest in off-pump coronary artery bypass grafting (OPCAB) has, in large part, been because of the detrimental effects of CPB; specifically the inflammation response, adverse neurologic outcomes, and the multi-system organ injury that may occur. Importantly, OPCAB has been associated with reduced myocardial enzyme release, lower transfusion requirement, reduced pulmonary and renal complications, shorter length of stay, and lower cost.(1,2) (SELECT FULL TEXT TO CONTINUE).

PMID: 22592901 [PubMed - as supplied by publisher]

Prevalence of Kawasaki Disease in Young Adults with Suspected Myocardial Ischemia.

Circulation. 2012 May 17;

Authors: Daniels LB, Tjajadi MS, Walford HH, Jimenez-Fernandez S, Trofimenko V, Fick DB, Phan HA, Linz PE, Nayak K, Kahn AM, Burns JC, Gordon JB

Abstract

BACKGROUND: Up to 25% of patients with untreated Kawasaki Disease (KD) and 5% of those treated with intravenous immunoglobulin will develop coronary artery aneurysms. Persistent aneurysms may remain silent until later in life when myocardial ischemia can occur. We sought to determine the prevalence of coronary artery aneurysms suggesting a history of KD among young adults undergoing coronary angiography for evaluation of possible myocardial ischemia. METHODS AND RESULTS: We reviewed the medical history and coronary angiograms of all adults under age 40 who underwent coronary angiography for evaluation of suspected myocardial ischemia at four San Diego hospitals from 2005-2009 (n=261). History of KD-compatible illness and cardiac risk factors (RF’s) were obtained by medical record review. Angiograms were independently reviewed for the presence, size, and location of aneurysms and CAD by two cardiologists blinded to the history. Patients were evaluated for number of RF’s, angiographic appearance of their coronary arteries, and known history of KD. Of the 261 young adults who underwent angiography, 16 had coronary aneurysms. After all clinical criteria were assessed, 5.0% had aneurysms definitely (n=4) or presumed (n=9) secondary to KD as the etiology of their coronary disease. CONCLUSIONS: Coronary sequelae of KD are present in 5% of young adults evaluated by angiography for myocardial ischemia. Cardiologists should be aware of this special subset of patients who may benefit from medical and invasive management strategies that differ from the treatment of atherosclerotic CAD.

PMID: 22595319 [PubMed - as supplied by publisher]

Newer Concepts Regarding Adults with Coronary Artery Aneurysms: Are They All Kawasaki? Does It Make a Difference?

Circulation. 2012 May 17;

Authors: Angelini P, Monge J

Abstract

The most commonly accepted definition of coronary aneurysm (CA) is an enlargement of a coronary arterial segment to more than 50% of the distal reference diameter.(1,2) This definition generally refers to the inner diameters of the vessels as determined by coronary angiography. Computerized axial tomographic (CAT) imaging is currently the preferred method of studying CA, especially for longitudinal studies of the extent and severity of dilatation, calcification, mural thrombosis, and stenosis.(3) Only tomographic imaging can quantitatively describe vascular wall thickening, a hallmark of the disease progression and prognosis in a post-arteritis CA.Additionally, the 50% definition can be inaccurate: in cases with diffuse dilatation, the reference diameter can become difficult to identify.(2) The 50% rule may or may not carry prognostic value, which is the main clinical goal of classifying a coronary segment as ectasic or anomalous. The essential clinical interest is in differentiating a CA from the Glagov phenomenon, the mild dilatation of the outer diameter of a coronary artery seen in early atherosclerotic degenerative disease. According to the Glacov theory, the outer diameter of the coronary arteries dilates in the early phases of atherosclerosis, when plaque deposition leads to positive remodeling with preservation of the vessel lumen.(4) Such positive remodeling probably does not allow for a dilatation of the coronary artery greater than 50% of the previous normal diameter. (SELECT FULL TEXT TO CONTINUE).

PMID: 22595320 [PubMed - as supplied by publisher]

Willingness of Kenyan HIV-1 serodiscordant couples to use antiretroviral based HIV-1 prevention strategies.

J Acquir Immune Defic Syndr. 2012 May 16;

Authors: Heffron R, Ngure K, Mugo N, Celum C, Kurth A, Curran K, Baeten JM

Abstract

INTRODUCTION:: Antiretroviral treatment (ART) and pre-exposure prophylaxis (PrEP) have demonstrated efficacy as new HIV-1 prevention approaches for HIV-1 serodiscordant couples. METHODS:: Among Kenyan HIV-1 serodiscordant heterosexual couples participating in a clinical trial of PrEP, we conducted a cross-sectional study and used descriptive statistical methods to explore couples’ willingness to use antiretrovirals for HIV-1 prevention. The study was conducted prior to July 2011, when studies among heterosexual populations reported that ART and PrEP reduced HIV-1 risk. RESULTS:: For 181 couples in which the HIV-1 infected partner had a CD4 count ≥350 cells/μL and had not yet initiated ART (and thus did not qualify for ART under Kenyan guidelines), 60.2% of HIV-1 infected partners (69.4% of men and 57.9% of women) were willing to use early ART (at CD4 ≥350 cells/μL) for HIV-1 prevention. Among HIV-1 uninfected partners, 92.7% (93.8% of men and 86.1% of women) reported willingness to use PrEP. When given a hypothetical choice of early ART or PrEP for HIV-1 prevention, 52.5% of HIV-1 infected participants would prefer to initiate ART early and 56.9% of HIV-1 uninfected participants would prefer to use PrEP. CONCLUSIONS:: Nearly 40% of Kenyan HIV-1 infected individuals in known HIV-1 serodiscordant partnerships reported reservations about early ART initiation for HIV-1 prevention. PrEP interest in this PrEP-experienced population was high. Strategies to achieve high uptake and sustained adherence to ART and PrEP for HIV-1 prevention in HIV-1 serodiscordant couples will require responding to couples’ preferences for prevention strategies.

PMID: 22595872 [PubMed - as supplied by publisher]

Racial/Ethnic Disparities in ART Adherence in the United States: Findings from the MACH14 Study.

J Acquir Immune Defic Syndr. 2012 May 16;

Authors: Simoni JM, Huh D, Wilson IB, Goggin K, Reynolds NR, Remien RH, Rosen MI, Bangsberg DR, Liu H

Abstract

BACKGROUND:: Minority race/ethnicity is generally associated with ART non-adherence in U.S.-based studies. Limitations of the existing literature include small samples, subjective adherence measures, and inadequate control for potential confounders such as mental health and substance use, which have been consistently associated with poorer adherence. METHODS:: Individual-level data were pooled from 13 US-based studies employing electronic drug monitoring to assess adherence. Adherence was operationalized as percent of prescribed doses taken from the first 12 (monthly) waves of data in each study. Depression symptoms were aggregated from several widely used assessments, and substance use was operationalized as any use of cocaine/stimulants, heroin/opiates, ecstasy, hallucinogens, or sedatives in the 30-365 days preceding baseline. RESULTS:: The final analytic sample of 1,809 participants ranged in age from 18 to 72 years and was 67% male. Participants were 53% African American, 14% Latino, and 34% White. In a logistic regression adjusting for age, gender, income, education, and site, race/ethnicity was significantly associated with adherence (p<.001), which persisted in a model that also controlled for depression and substance use (p<.001), with African Americans having significantly lower adherence than Latinos (OR=0.72, p=.04) and Whites (OR=0.60, p<.001). Adherence did not differ between Whites and Latinos (OR=0.86, p=.28). CONCLUSIONS:: Racial/ethnic differences in demographics, depression, and substance abuse do not explain the lower level of ART adherence in African Americans observed in our sample. Further research is needed to explain the persistent disparity and might examine factors such as mistrust of providers, health literacy, and inequities in the health care system.

PMID: 22595873 [PubMed - as supplied by publisher]

Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial.

Gut. 2012 May 17;

Authors: Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, Wehkamp J, Feagan BG, Yao MD, Karczewski M, Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei M, Bertolino AP, Tougas G, Travis SP,

Abstract

ObjectiveThe authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn’s disease.DesignIn a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response.Results59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (CDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected).ConclusionsBlockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo.Clinical trial registrationThis trial was registered at ClinicalTrial.gov with the number NCT01009281.

PMID: 22595313 [PubMed - as supplied by publisher]

Surgeon-related variance: how much longer for its recognition?

Gut. 2012 May 17;

Authors: Fielding LP, Grace R, Hittinger R

PMID: 22595314 [PubMed - as supplied by publisher]

Suicidality and sexual orientation among men in Switzerland: Findings from 3 probability surveys.

J Psychiatr Res. 2012 May 14;

Authors: Wang J, Häusermann M, Wydler H, Mohler-Kuo M, Weiss MG

Abstract

Few population-based surveys in Europe have examined the link between suicidality and sexual orientation. The objective of this study was to assess the prevalences of and risk for suicidality by sexual orientation, especially among adolescent and young adult men. Data came from three probability-based surveys in Switzerland from 2002: 1) Geneva Gay Men’s Health Survey (GGMHS) with 571 gay/bisexual men, 2) Swiss Multicenter Adolescent Survey on Health (SMASH) with 7,428 16-20 year olds, and 3) Swiss Recruit Survey (ch-x) with 22,415 new recruits. In GGMHS, suicidal ideation (12 months/lifetime) was reported by 22%/55%, suicide plans 12%/38%, and suicide attempts 4%/19%. While lifetime prevalences and ratios are similar across age groups, men under 25 years reported the highest 12-month prevalences for suicidal ideation (35.4%) and suicide attempts (11.5%) and the lowest attempt ratios (1:1.5 for attempt to plan and 1:3.1 for attempt to ideation). The lifetime prevalence of suicide attempts among homo/bisexual men aged 16-20 years varies from 5.1% in ch-x to 14.1% in SMASH to 22.0% in GGMHS. Compared to their heterosexual counterparts, significantly more homo/bisexual men reported 12-month suicidal ideation, plans, and attempts (OR = 2.09-2.26) and lifetime suicidal ideation (OR = 2.15) and suicide attempts (OR = 4.68-5.36). Prevalences and ratios vary among gay men by age and among young men by both sexual orientation and study population. Lifetime prevalences and ratios of non-fatal suicidal behaviors appear constant across age groups as is the increased risk of suicidality among young homo/bisexual men.

PMID: 22591853 [PubMed - as supplied by publisher]

Smaller volumes of caudate nuclei in prepubertal children with ADHD: Impact of age.

J Psychiatr Res. 2012 May 15;

Authors: Carrey N, Bernier D, Emms M, Gunde E, Sparkes S, Macmaster FP, Rusak B

Abstract

OBJECTIVE: Age-related abnormalities in caudate volumes have been reported to differ across the periods of childhood and puberty in children with ADHD. This study assessed caudate volumetric abnormalities across two narrow age clusters within the childhood period. METHOD: Three-dimensional manual tracings of the head and body of the caudate nucleus and of the cerebrum were acquired from 26 medication-naïve boys with a diagnosis of ADHD (ages 5.9-10.8 years), and 24 age-matched normal controls. RESULTS: Boys with ADHD had smaller total caudate volumes relative to controls, F(1,48)=4.29, p=0.04. Adjustment of caudate volumes with respect to age demonstrated that this group difference was driven solely by participants in the 5.9-7.3 year range, F(1, 46)=5.64, p=0.022, with an effect size of d=0.69. No Group effect was found in older participants, F(1, 46)=0.82, p=0.37. CONCLUSIONS: These novel findings suggest a different pattern of caudate volume abnormalities across narrow age clusters prior to puberty in boys with ADHD. Anatomical differences in brain structures related to ADHD in prepubertal children should be evaluated with respect to the changing developmental trajectory of brain regions within this period of rapid brain growth.

PMID: 22595868 [PubMed - as supplied by publisher]

Negative expectancies in posttraumatic stress disorder: Neurophysiological (N400) and behavioral evidence.

J Psychiatr Res. 2012 May 15;

Authors: Kimble M, Batterink L, Marks E, Ross C, Fleming K

Abstract

BACKGROUND: Posttraumatic stress disorder (PTSD) is a disorder that theoretically and clinically is thought to be associated with persistent and exaggerated negative expectancies. This study used the N400 event-related potential (ERP) to investigate expectancies for threatening endings to ambiguous sentence stems. The N400 ERP is thought to reflect the amount of effort required to integrate a stimulus into a given context. In sentence reading tasks, the N400 is reliably larger when a word is unexpected. METHOD: In this study, fifty-seven trauma survivors of various types (22 with PTSD and 35 without) read ambiguous sentence stems on a computer screen. These sentence stems were completed with either an expected (“The unfortunate man lost his…wallet”), unexpected (“The unfortunate man lost his…artist”), or threatening word endings (“The unfortunate man lost his…leg”). RESULTS: Participants with PTSD, as compared to those without, showed significantly smaller N400s to threatening sentence endings suggesting enhanced expectancies for threat. Behavioral responses supported this conclusion. CONCLUSIONS: These findings are consistent with the clinical presentation of hypervigilance and proposed revisions to the DSM-V that emphasize persistent and exaggerated negative expectations about one’s self, others, or the world. Relative to earlier behavioral studies, this work further suggests that this expectancy bias occurs automatically and at the early stages of information processing. The discussion focuses on the potential impact of a negative expectancy bias in PTSD and the value of the ambiguous sentence paradigm for studying PTSD as well as other disorders.

PMID: 22595869 [PubMed - as supplied by publisher]

Alcohol and cannabis use and mortality in people with schizophrenia and related psychotic disorders.

J Psychiatr Res. 2012 May 15;

Authors: Koola MM, McMahon RP, Wehring HJ, Liu F, Mackowick KM, Warren KR, Feldman S, Shim JC, Love RC, Kelly DL

Abstract

The impact of co-morbid substance use on mortality is not well studied in psychotic disorders. The objective of this study was to examine the impact of substance use on mortality in people with psychotic disorders and alcohol and/or drug use. We examined the rate of substance use and the risk of substance use on mortality risk over a 4-10 year period in 762 people with psychotic disorders. Deceased patients were identified from the Social Security Death Index and the Maryland Division of Vital Records. Substance use was defined as regular and heavy use or abuse or dependence. Seventy seven percent had co-morbid lifetime substance use, with co-morbid cannabis and alcohol use occurring most commonly. Out of 762 subjects, 62 died during follow up. In a Cox model, predicted mortality risk was higher in age group 35-55 compared to <35 years and in males, but reduced in cannabis users. Overall five- (3.1% vs 7.5%) and ten-year mortality risk (5.5% vs. 13.6%) was lower in cannabis users than in non-users with psychotic disorders (p = 0.005) in a survival model. Alcohol use was not predictive of mortality. We observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments. Future research is warranted to replicate these findings and to shed light on the anti-inflammatory properties of the endocannabinoid system and its role in decreased mortality in people with psychotic disorders.

PMID: 22595870 [PubMed - as supplied by publisher]

Region-specific glutamate changes in patients with unipolar depression.

J Psychiatr Res. 2012 May 15;

Authors: Grimm S, Luborzewski A, Schubert F, Merkl A, Kronenberg G, Colla M, Heuser I, Bajbouj M

Abstract

The present study aimed to investigate glutamate concentrations in patients with unipolar depression in the midcingulate cortex (MCC) as compared to the left dorsolateral prefrontal cortex (DLPFC). We hypothesized a dissociation of glutamate levels with unchanged levels in DLPFC and abnormally changed levels in MCC as well as differential effects of antidepressant pharmacotherapy. Glutamate was determined using magnetic resonance spectroscopy at 3 T in DLPFC and MCC in fourteen depressed patients and matched healthy volunteers. A follow-up measurement was performed after 4 weeks of antidepressant treatment. The main finding is a region-specific pattern of glutamate concentrations with increased MCC glutamate concentrations and no significant differences in DLPFC glutamate concentrations in unipolar depressive patients compared to healthy controls. Response and non-response to antidepressant pharmacotherapy were predicted by high glutamate at baseline in DLPFC and MCC, respectively. In addition, treatment responders showed a further increase in DLPFC glutamate levels after successful antidepressant treatment. Findings indicate altered region-specific glutamate concentrations in DLPFC and MCC that are predictive of response and non-response, respectively, to antidepressant pharmacotherapy. These findings might serve as a starting point for future studies in which the value of this metabolite pattern for treatment response prediction should be investigated.

PMID: 22595871 [PubMed - as supplied by publisher]

Reviewers Who Completed a Review During 2011.

Arch Gen Psychiatry. 2012 Apr 1;:1-8

Authors: Coyle JT

PMID: 22605542 [PubMed - as supplied by publisher]

A novel internalization motif regulates human IFN-γR1 endocytosis.

J Leukoc Biol. 2012 May 17;

Authors: Yancoski J, Sadat MA, Aksentijevich N, Bernasconi A, Holland SM, Rosenzweig SD

Abstract

This study tested the hypothesis that the IFN-γR1 287-YVSLI-91 intracellular motif regulates its endocytosis. IFN-γ exerts its biological activities by interacting with a specific cell-surface RC composed of two IFN-γR1 and two IFN-γR2 chains. Following IFN-γ binding and along with the initiation of signal transduction, the ligand and IFN-γR1 are internalized. Two major types of consensus-sorting signals are described in receptors, which are rapidly internalized from the plasma membrane to intracellular compartments: tyrosine-based and dileucine-based internalization motifs. Transfection of HEK 293 cells and IFN-γR1-deficient fibroblasts with WT and site-directed, mutagenesis-generated mutant IFN-γR1 expression vectors helped us to identify region IFN-γR1 287-YVSLI-291 as the critical domain required for IFN-γ-induced IFN-γR1 internalization and Y287 and LI290-291 as part of a common structure essential for receptor endocytosis and function. This new endocytosis motif, YxxLI, shares characteristics of tyrosine-based and dileucine-based internalization motifs and is highly conserved in IFN-γRs across species. The IFN-γR1 270-LI-271 dileucine motif, previously thought to be involved in this receptor endocytosis, showed to be unnecessary for receptor endocytosis.

PMID: 22595141 [PubMed - as supplied by publisher]

Staphylococcus aureus directly activates eosinophils via platelet-activating factor receptor.

J Leukoc Biol. 2012 May 17;

Authors: Hosoki K, Nakamura A, Nagao M, Hiraguchi Y, Tanida H, Tokuda R, Wada H, Nobori T, Suga S, Fujisawa T

Abstract

Colonization by SA is associated with exacerbation of AD. Eosinophilic inflammation is a cardinal pathological feature of AD, but little is known about possible direct interaction between SA and eosinophils. PAFR appears to be involved in phagocytosis of Gram-positive bacteria by leukocytes. The objective of this study was to investigate whether SA directly induces eosinophil effector functions via PAFR in the context of AD pathogenesis. Peripheral blood eosinophils were cultured with heat-killed SA, and EDN release, superoxide generation, and adhesion to fibronectin-coated plates were measured. Cytokines, released in the supernatants, were quantified by multiplex bead immunoassays. FISH-labeled SA was incubated with eosinophils and visualized by confocal laser-scanning microscopy. PAFR-blocking peptide and PAFR antagonists were tested for inhibitory effects on SA-induced reactions. SA induced EDN release and superoxide generation by eosinophils in a dose-dependent manner. IL-5 significantly enhanced SA-induced EDN release. IL-5 and IL-17A significantly enhanced SA-induced superoxide generation. SA enhanced eosinophil adhesion to fibronectin, which was blocked by anti-CD49d, and induced eosinophil secretion of various cytokines/chemokines (IL-2R, IL-9, TNFR, IL-1β, IL-17A, IP-10, TNF-α, PDGF-bb, VEGF, and FGF-basic). After incubation of eosinophils with SA, FISH-labeled SA was visualized in the eosinophils’ cytoplasm, indicating phagocytosis. A PAFR-blocking peptide and two PAFR antagonists completely inhibited those reactions. In conclusion, SA directly induced eosinophil activation via PAFR. Blockade of PAFR may be a novel, therapeutic approach for AD colonized by SA.

PMID: 22595142 [PubMed - as supplied by publisher]